Drug resistance among bacterial pathogens is becoming a serious health problem worldwide. Since the basic mechanism for resistance to many existing antibacterials is already widespread, the health care industry is currently in severe need of novel, mechanistically distinct antibacterials. To date, none of the commercially available antibacterials target any of the components of the replication system in bacteria. Since DNA replication is essential for the propagation of bacteria, such compounds would represent a novel class of antibacterial drugs. The overall aim of this project is to identify a diverse set of small molecules that inhibit targets within a replication system. A fluorescence-based assay will be set up in a high-throughput screening format in which synthesis of DNA is dependent on the coordinated function of 12 protein components of the E. coli replication apparatus. Initial screen will sample a chemical library consisting of approximately 5,000 molecules. For several most active compounds, in vitro potency will be established and targets within the replication system identified. This work will form the basis for an expanded screen of larger compound libraries and lead optimization of promising antibacterial drug candidates within the two-year phase II period.
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